The present invention relates to processes and formulations capable of protecting, stabilizing, and/or delivering one or more bio-affecting compounds. More particularly, the invention relates to processes of making a composition having a host compound capable of accepting one or more bio-affecting guest compounds and new compositions formed by the processes. The processes are particularly useful in formulating compositions for the topical delivery of the bio-affecting compounds.
Biological systems depend on a balance between water-soluble compounds and fat-soluble compounds. Frequently, natural enzymatic reaction will convert a compound to help maintain the balance between water-soluble compounds and lipid-soluble compounds in the biological system, for example, ascorbyl palmitate, which is lipid soluble, can be converted by enzymatic action to ascorbic acid, which is water soluble.
The flow of both water-soluble and lipid-soluble compounds into and out of biological systems are controlled by cell membranes. To penetrate a membrane, a compound needs to have an appropriate structure. In addition, the transfer of the compound across a cell membrane is governed by enzymes, pH, and salt balance. Thus, the cell membranes also help maintain the balance between water-soluble compounds and lipid-soluble compounds in the biological system.
The formation of compositions capable of delivering a compound to a cell membrane and in a structural form or environment that will encourage the transfer of the compound across the cell membrane into the biological system has been the subject of considerable research using many different approaches.
For example, it is known that ascorbic acid (Vitamin C) can be beneficial for healing the skin. In a composition for topical application to the skin, a relatively high concentration of ascorbic acid, preferably at least 8% by weight of the composition, is desirable, and perhaps necessary, to be effective in penetrating the dermal layer and activating collagen in the skin. When the ascorbic acid composition is exposed to air, however, and particularly at such high concentrations, the ascorbic acid tends to rapidly oxidize. A stabilizing environment for the ascorbic acid is necessary to protect it from oxidation or the composition will lose its effectiveness.
It is also known that alpha tocopherol (Vitamin E) can be beneficial for healing and/or preventing damage to the skin by scavenging free radicals in the biological system. In a composition for topical application to the skin, a relatively high concentration of alpha tocopherol, preferably at least 5% by weight of the composition, is desirable, and perhaps necessary, to be effective in penetrating the dermal layer and reducing free radicals. When the alpha tocopherol composition is exposed to air, however, the alpha tocopherol tends to oxidize, that is, become rancid. A stabilizing environment for the alpha tocopherol is necessary to protect it from becoming rancid or the composition will lose its effectiveness.
Considerable research has been conducted on stabilizing ascorbic acid, which is water soluble, and on stabilizing alpha tocopherol, which is lipid soluble. Because of their widely-different solubility characteristics, however, obtaining high concentrations of both in the same composition continues to be a particular challenge. Many compositions for topical application contain low concentrations of both ascorbic acid (as a preservative) and alpha tocopherol (as an antioxidant) at levels below 0.5% by weight. At these low concentrations, however, the ascorbic acid and alpha tocopherol are much less effective in repairing skin damage.
Furthermore, compositions having high concentrations of certain bio-affecting compounds, such as ascorbic acid, have been particularly difficult to stabilize. In this regard, standard stability test procedures that are used to determine the shelf life of a product do not tell the whole story. A standard stability test is conducted at elevated temperatures and humidity is commonly used for determining the shelf life of a composition. Because the rates of chemical reactions and the growth of bacteria tend to double with each 10xc2x0 C. (18xc2x0 F.) increase in temperature, testing the stability of a product at elevated temperatures can be used to calculate its expected shelf life at ordinary temperatures with a reasonable degree of confidence. The standard test requires the compound to be placed in the sealed container in which it is to be sold or stored, for 30, 60, and 90 days at 31xc2x0 C. (87xc2x0 F.) and at 45xc2x0 C. (113xc2x0 F.) in a chamber at 80% relative humidity. This test does not, however, determine the stability of the product after the sealed container has been opened. Unfortunately, many products that pass the shelf-life stability test become unstable in a much shorter period of time once the container has been opened, and quickly lose effectiveness, and worse, may allow the growth of pathogenic bacteria.
Another type of problem encountered in designing topical delivery systems for bio-affecting compounds is encountered when the bio-affecting compound is virtually or totally insoluble in either water or lipids. For example, bio-affecting ingredients for ultra-violet sun block protection include zinc oxide (ZnO) and/or titanium dioxide (TiO2), lo which can be used for blocking UV-A and/or UV-B radiation, respectively. Unfortunately, it is difficult to find a carrier for evenly dispersing these insoluble inorganic compounds in a sufficient concentration to form a protective layer over the skin without also imparting a whitening color, which most people find aesthetically undesirable.
There has been a long-felt need for a process of formulating a composition that would be capable of stabilizing at least two different bio-affecting compounds having diverse solubility characteristics. Such a process can be used to stabilize only one bio-affecting compound, but it is expected to have particularly beneficial use when it is desirable to prepare a composition having at least two different bio-affecting compounds of diverse solubility characteristics. There has also been a long-felt need for a process of formulating a composition that is capable of protecting and stabilizing high concentrations of certain bio-affecting compounds that have been particularly difficult to stabilize at such high concentrations. In addition, there has been a particular long-felt need for a process of formulating a composition that is capable of remaining stable for long periods of time, even after the container has been opened causing the composition to be exposed to the ambient air environment. It would also be desirable to produce a composition that discourages the growth of bacteria. These problems have been particularly acute with respect to compositions and products that are expected to be used over an extended period of time after the sealed container has been opened. By way of further example, there has been a long-felt need for a topical delivery system capable of evenly dispersing a bio-affecting compound that is insoluble.
The formulation processes and compositions according to the invention depend on the initial formation of a host composition having a host capable of accepting a guest in host-guest coordination. One or more bio-active compounds can then be mixed with the host composition for creation of a stable molecular environment, that is, according to a process of molecular stacking. For compositions including water, the formulation processes preferably include establishing a desired pH range to help maintain the stability of pH-sensitive compounds. A wide range of bio-affecting compositions can be made according to the general approach of the invention. In addition, specific formulation processes and compositions are provided.
According to a general aspect of the invention, a process is provided for making a host composition having a host for at least one guest, the process comprising mixing, in any order:
(i) a non-ionic surfactant selected from the group consisting of compounds having a chemical structure: 
where xe2x80x9cxe2x80x94CHxe2x80x94Oxe2x80x94CHxe2x80x94xe2x80x9d represents an epoxide group,
where Ra and Rb are hydrocarbons that can be the same or different,
where at least one of the Ra and Rb hydrocarbons includes an epoxide group within 3 carbons of the hydrocarbon attachment to contribute to the desired hydro-lipid balance of 7-9,
where Rc is hydrogen or a methyl group, and
where Rd is a methylene group (xe2x80x94CH2xe2x80x94), an ethyl group (xe2x80x94CH2xe2x80x94CH2xe2x80x94), or
a structurally equivalent link with a bond length range about the same as or shorter than that provided by an ethyl group, and
having a hydro-lipid balance in the range of 7-9,
or any combination of two or more thereof;
(ii) in a stoichiometric proportion of at least 1:6 relative to the non-ionic surfactant, an amphoteric surfactant selected from the group consisting of organic compounds having the chemical formula NH3xe2x80x94Rxe2x80x94COOH, where R is a straight, branched, or aromatic hydrocarbon structure having 6-24 carbons, or any combination of two or more thereof;
(iii) at least a sufficient amount of a solvent to dissolve the amphoteric surfactant, the solvent comprising one or more compounds selected from the group consisting of water, alcohols having straight or branched hydrocarbon structure having up to 6 carbons, glycosamionoglucans, or any combination of two or more of the foregoing:
(iv) in a stoichiometric proportion of at least 1:240 relative to the non-ionic surfactant, an aromatic selected from the group consisting of compounds having at least one aromatic five or six-member ring structure, or any combination of two or more thereof.
(v) in a stoichiometric proportion of at least 1:240 relative to the non-ionic surfactant, of an aluminum cation;
(vi) in a stoichiometric proportion of at least 1:1200 relative to the non-ionic surfactant of at least one Lewis acid that is not a Bronsted-Lowry acid;
(vii) at least 0.003 molar concentration of at least one Bronsted-Lowry acid.
Without being limited by suggesting a theoretical explanation at the molecular level for how these ingredients react to create a host composition, it is believed that a process according to this general approach is capable of producing a composition having one or more host molecular complexes such as crown ethers, crystahemispherands, calixerands, calixarenes, carcerands, rotoxanes or other host molecular configurations capable of forming a host-guest relationship with guest molecular structures, which is accomplished without the use of a guest transitional metal. Instead of a transition metal, it is believed that a five- or six-member aromatic ring structure is of the appropriate molecular size and provides the appropriate electron orbitals to coordinate in the formation of the host complex. After the initial formation of a host composition having a host complex, a bio-affecting compound, either organic or inorganic, can be mixed with the host composition according to the formulation processes for creation of a stable molecular environment, that is, according to a process of molecular stacking.
The particular compounds used can be varied according to the principles of the invention dependent on the desired molecular stacking parameters for stabilizing one or more bio-affecting ingredients. For example, nonoxyl-9, which includes a phosphate group that can be considered to be a Lewis acid but not a Bronsted-Lowry acid, can be used for providing both the aromatic and the Lewis acid. Nonoxyl-9 has the further advantage of being a well-known germicide. By way of another example, in a composition including water, aluminum sulfate, which in water forms a small amount of sulfuric acid, can be used for providing both the aluminum cation and the Bronsted-Lowry acid.
As will hereinafter be described in more detail, and illustrated by way of representative examples, the relative proportions of these compounds can vary considerably without departing from the scope of the invention.
According to a further aspect of the invention, one or more compounds are selected to be sequentially mixed with the host composition to form a stable molecular environment, which is sometimes referred to herein as a process of molecular stacking. The sequence of mixing the additional bio-affecting compounds is based on the following factors:
(i) the one or more desired bio-affecting compounds to be added to create a desired composition for a specific application; and
(ii) the desired point of attachment to the host complexes.
The systematic addition, i.e., molecular stacking, of the bio-affecting and other desirable ingredients into the host composition is also based on a consideration of the following factors:
(i) the molecular structure of each ingredient;
(ii) the solubility of each ingredient compound and the hydro-lipid balance of the composition, and the possibility of changing the solubility characteristics by changing the form of the ingredient, e.g., by using a salt form of the ingredient;
(iii) in an aqueous composition, the effect of each ingredient on the pH, and the sensitivity of each ingredient to pH; and
(iv) the temperature required for xe2x80x9csettingxe2x80x9d or xe2x80x9cstackingxe2x80x9d the ingredient into the host composition.
In formulation processes including water, the process preferably includes establishing a desired pH range to help maintain the stability of pH-sensitive compounds. Establishing the desired pH range often has a substantial influence on the selection of one or more additional compounds to be mixed with the host composition and the mixing sequence.
Those skilled in the art will appreciate that a wide range of bio-affecting compositions can be made according to the general approach of the invention. In addition, specific formulation processes and compositions are provided for various bio-affecting compositions, which compositions are highly effective for certain biological purposes, such as skin exfoliation, collagen activation in the skin, the topical delivery of salicylic acid, and other pain relievers to local areas of pain and/or inflammation, to promote skin healing processes, and other purposes, such as the delivery of plant growth hormones, such as diterpenes, or even the topical dispersion of UV radiation blocking compounds. Thus, the formulation processes according to the invention are expected to be useful in the production of a wide array of compositions having bio-affecting purposes.
As used herein, water soluble means that a compound or mixture of compounds has a solubility characteristic of at least 0.2 g/100 g of distilled water at standard temperature and pressure. To the extent the compound or mixture of compounds does not meet this solubility criteria, it would be expected to be lipid soluble. It is to be understood that this bright-line criteria between water solubility and lipid solubility is arbitrarily assigned as a matter of clarity of definition, and that the solubility characteristics in relation to complex mixtures can be blurred by factors such as temperature, pressure, pH, chemical reaction, complex coordination, and mutual solubility. Of course, some compounds, particularly inorganic compounds, can be nearly or completely insoluble in both water and lipids.
For example, a process according to the invention can be used to formulate specific compositions including one or more compounds that can be considered to be water soluble selected from the group consisting of: ascorbic acid, ascorbyl salts, 7-dehydroxy cholesterol, alpha-hydroxy acids, beta-hydroxy acids, glycolic acids, isoprenoids, bioflavinoids, fatty acids, glycosaminoglucans, flavin mono nucleotides, flavin mono nucleotide derivatives, diterpenes, glycerophospholipids, beta-carotene, trans retinol, trans retinoic acid, allontoin, nonoxyl-9, betaine, and any combination of two or more of the foregoing.
A process according to the invention can be used to formulate specific compositions including one or more compounds that can be considered to be lipid-soluble selected from the group consisting of: alpha tocopherol, alpha tocopherol ester, co-enzymes, ubiquinones, menaquinones, phylloquinones, 7-dehydroxycholesterol, steroids, bioflavinoids. terpenes, saponified fatty acids, unsaponified fats, alycerophospholipids, and any combination of two or more of the foregoing.
Similarly, the host complexes can be used for a variety of formulations that do not require direct activation of ingredients in response to the system in which they arc introduced. Rather, the stabilization of crown complexes can provide an alternative at the other end of the spectrum of products. By way of further example, a process according to the invention can be used to formulate specific compositions including one or more compounds that can be considered to be nearly or completely insoluble in either water and lipids, such as inorganic compounds, and more particularly, titanium dioxide and/or zinc oxide. The processes according to the invention allow for the inclusion of non-hydrocarbon chemicals that are bio-affecting as not only resistant to external forces (like UV radiation) within mammalian systems, but also provide the consistent ability to release other organic products as a resultant of the interacting system.
It is important to note, however, that solubility characteristics of chemical compounds are typically reported based on studies of a purified form of the particular chemical. Many naturally-occurring chemicals are found and extracted in conjunction with derivatives that substantially affect solubility of the naturally-occurring mixtures.
The invention has one or more of the following illustrative objects, which are not intended to limit the invention to being able to accomplish all of the following objects:
(a) to provide a host composition having a host capable of accepting at least one bio-affecting guest for use in topical delivery of the bio-affecting guest to the mammalian skin/dermal layer or plant membrane of a target biological system;
(b) to provide a host composition capable of stabilizing a sufficiently high concentration of one or more bio-affecting compounds to activate the natural biochemical pathways after delivery to and penetration through the mammalian ski n/dermal layer or plant membrane of a target biological system;
(c) to create a molecular environment that is capable of protecting and stabilizing at least two bio-affecting compounds that have widely-different solubility characteristics:
(d) to create a molecular environment and coordinated complex that will release one or more bio-affecting compounds to the membrane of a target biological system; and/or
(e) to provide specific formulations and compositions for the topical delivery of the bio-affecting compounds.